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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 3  |  Page : 179-183

Safety and effectiveness of angiotensin receptor-neprilysin inhibitors in Indian patients with heart failure with preserved ejection fraction – “ARNI-PRESERVED” study


1 Department of Cardiology, Yashoda Hospitals, Hyderabad, Telangana, India
2 Department of Internal Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
3 Department of Nephrology and Transplant Medicine, Yashoda Hospitals, Hyderabad, Telangana, India

Date of Submission04-Sep-2021
Date of Decision17-Oct-2021
Date of Acceptance10-Nov-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. Pankaj Jariwala
Department of Cardiology, Yashoda Hospitals, Somajiguda, Raj Bhavan Road, Hyderabad - 500 082, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_95_21

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  Abstract 


Background: The goal of this study is to look at the safety and efficacy of angiotensin receptor-neprilysin inhibitors (ARNI) (valsartan/sacubitril), a combination of angiotensin II receptor blocker and neprilysin inhibitor ARNI, in patients with heart failure with preserved ejection fraction (HFpEF).
Materials and Methods: Between June and December 2020, retrospective research was conducted on a study participant of primarily angiographically confirmed computer-aided design patients who underwent complete revascularization. A total of 154 HFpEF patients (87 females and 67 males) were treated with ARNI, which was subsequently titrated up to a maximum tolerable dose and monitored in an outpatient clinic. Fifty-six patients were given ARNI while in the hospital for decompensated heart failure before being discharged.
Results: Patients were categorized as the New York Heart Association (NYHA) class III (71.4%) and NYHA class II (28.6%). Diabetes mellitus was identified in 52% of patients, while hypertension was found in 78%. Symptomatic clinical improvement was observed, with a substantial decrease in NYHA class down to NYHA class II (P = 0.018). A considerable decrease in NYHA class resulted in symptomatic clinical improvement as well as the rales and peripheral edema had resolved (P < 0.001). The NT-pro-BNP levels were considerably lowered (P < 0.001). The echocardiographic parameters for diastolic function (E/A, E/E' ratios) improved. In individuals with HFpEF, ARNI resulted in significant clinical benefits.
Conclusion: In individuals with HFpEF, sacubitril/valsartan, ARNI resulted in significant clinical benefits. A randomized research is also required to see if it results in beneficial outcomes for a wider sample.

Keywords: Angiotensin receptor-neprilysin inhibitor, heart failure with preserved ejection fraction, sacubitril/valsartan


How to cite this article:
Jariwala P, Punjani A, Boorugu H, Madhawar DB, Jadhav K. Safety and effectiveness of angiotensin receptor-neprilysin inhibitors in Indian patients with heart failure with preserved ejection fraction – “ARNI-PRESERVED” study. Heart India 2021;9:179-83

How to cite this URL:
Jariwala P, Punjani A, Boorugu H, Madhawar DB, Jadhav K. Safety and effectiveness of angiotensin receptor-neprilysin inhibitors in Indian patients with heart failure with preserved ejection fraction – “ARNI-PRESERVED” study. Heart India [serial online] 2021 [cited 2022 Jan 28];9:179-83. Available from: https://www.heartindia.net/text.asp?2021/9/3/179/333297




  Introduction Top


Heart failure with preserved ejection fraction (HFpEF), formerly termed diastolic heart failure (HF) (ejection fraction [EF] >50%), worsens with aging and is more frequent in older hypertensive women.[1],[2] However, there is a void in existing knowledge of its fundamental pathophysiological mechanisms. Left ventricular (LV) hypertrophy and fibrosis, mild LV systolic dysfunction, altered diastolic relaxation and atrioventricular coupling, enhanced cardiomyocyte stiffness, and systemic inflammation are among the pathophysiological factors.[3] Angiotensin receptor-neprilysin inhibitors (ARNI) decrease the hazard of cardiovascular (CV) death and hospitalization in patients with chronic heart failure with reduced ejection fraction (HFrEF) (New York Heart Association [NYHA] Class II-IV).[4] Although there are several evidence-based therapies for HFrEF, there is no effective therapy for HFpEF presently. ARNI demonstrated minimal evidence of additional improvements in patients with HFpEF.[5] As a result, the purpose of this study is to investigate the safety and efficacy of ARNI in Indian patients with HFpEF.


  Materials And Methods Top


Study population

The study was a retrospective, single-center analysis that looked at the efficacy and safety of ARNI in Indian patients with HFpEF between June and December 2020. All patients had coronary angiography to rule out computer-aided design (CAD), and only those with significant CAD after complete revascularization were included in the study. The protocol advocated that mineralocorticoid receptor antagonists can be used in all patients, considering renal function, serum potassium, and tolerability. A total of 154 HFpEF patients were enrolled. ARNI was prescribed to 98 patients on an outpatient department (OPD) basis, and 56 patients were administered before discharge to those who were admitted for decompensated HF if they met the inclusion and exclusion criteria as shown in [Table 1].
Table 1: Inclusion and exclusion criteria of the study

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Follow-up

In the OPD, every patient had periodic blood pressure, heart rate, renal profile, and potassium levels measured. Patients were seen in the HF department every 4-weeks after starting ARNI and with each dose change for up to 3-months, and afterward on a regular 2-months interval for the next 3-months. At each follow-up visit, patients were assessed for clinical improvement in NYHA class, resolution of pedal edema, rales, and the development of angioedema. At the initial visit and 6-months, laboratory measures such as renal function tests and NT-pro-BNP levels, as well as other echocardiographic parameters of LV diastolic function, were measured. Echocardiographic measurements were obtained using a Philips Epiq ultrasound machine.

Statistical evaluation

The analysis was carried out entirely with the help of the IBM SPSS software, USA. Absolute numbers and percentages were used to illustrate categorical data. Means and standard deviations were used to represent continuous data. For categorical variables, the Chi-square test or Fisher's exact test was used, while for continuous variables, the t-test was used.


  Results Top


The study looked at data from 154 patients aged 65.6 ± 18.4 years, with 56.5% of them being females. The baseline parameters, concomitant comorbid disorders, revascularization, and specific information on the pharmacological treatment provided in conjunction with ARNI are summarized in [Table 2]. During the follow-up period, 16.8% of patients were up-titrated to the target dose of 200 mg twice daily, whereas most patients tolerated the dose of 100 mg twice daily in 58.8% of cases. The average dose of the diuretic (torsemide) was 10 mg.
Table 2: Demographics, concurrent comorbid conditions, and medications prescribed to heart failure with preserved ejection fraction patients, along with angiotensin receptor neprilysin inhibitors

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All treated patients had a significant reduction in HF symptoms as measured by the NYHA functional class and physical signs such as pedal edema, rales [P < 0.001; [Figure 1]], as well as a significant reduction in mean NT-proBNP levels, dropping from 1607.8 ± 304.6 to 444.3 ± 234.9 pg/mL (P < 0.001). There were significant changes in mean systolic blood pressure, diastolic blood pressure, heart rate (P < 0.001). The echocardiographic parameters of diastolic dysfunction demonstrated a significant reduction of E/A, E/E' ratios (P = 0.013; 0.006 respectively), and pulmonary hypertension (P < 0.001) as shown in [Table 3]. There was no hospitalization for HF or deaths reported during follow-up.
Figure 1: Comparison of New York Heart Association class and physical signs at initial visit and 6-months after administration of angiotensin II receptor blocker and neprilysin inhibitor for patients with heart failure with preserved ejection fraction

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Table 3: Comparison of vital parameters, laboratory results, and echocardiographic parameters at the initial visit and 6-months follow-up

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  Discussion Top


Conventional HFpEF therapeutic strategies focused on the administration of RAAS inhibitors and diuretics without addressing the associated comorbidities. The purpose of the study was to evaluate Indian patients with HFpEF their therapeutic objectives and outcomes, which were not uniform, probably due to the regional variation of HFpEF patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial.[6] An analysis of ARNI studies indicates that it improves protection against cardio-cerebrovascular events by lowering pulse pressure, which is an important determinant of CV incidents such as myocardial infarction, HF, and CV death.[7] After 36 weeks, ARNI alleviated global circumferential but not longitudinal strain when matched to valsartan, an angiotensin II receptor blocker (ARB).[8]

Contrasting to the findings of the current study, Solomon et al. discovered that CV mortality contributes to 8.5% of all death. It revealed no notable advantage for ARNI in terms of reduced rehospitalization in HF patients with an EF of ≥45%.[9] However, Solomon et al. found that ARNI is more beneficial than other renin-angiotensin-aldosterone–system inhibitors (angiotensin-converting enzyme inhibitors/ARBs) for female HF patients hospitalization independent of EF, lending credence to the current study results.[10]

Our research study was favorable in contrast to the PARAGON-HF trial because mortality was included in the primary combined outcome in the PARAGON-HF trial, and HFpEF seems to be more likely to suffer from comorbid conditions such as infections, renal failure, and stroke and less probable to die from cardiac causes.

Study limitations

The small cohort size, limited follow-up duration, biomarkers, and echocardiographic characteristics all hampered this retrospective observational investigation. Furthermore, due to the lack of a control group, it lacks to resolve therapeutic benefit in the examined patients because of the action of ARNI. It is, however, seen as the start of a management shift away from established objectives and toward novel indications for the use of ARNI in the treatment of HFpEF in real-life situations. Furthermore, larger research should include a comparison group to demonstrate that clinical improvement in patients was attributable to the action of ARNI on a broader sample.


  Conclusion Top


The current study looked at the efficacy and safety of ARNI in these individuals and discovered that it has different CV and renal effects in patients with HFpEF. These findings give support for a developing outcome-improving therapy approach that is superior to the existing medications employed in HFpEF patients. Following the completion of this feasibility study, the researcher plans to encourage collecting prespecified patients with larger sample size and an extended follow-up period. Furthermore, larger research should include a comparison group to demonstrate that clinical improvement in patients was attributable to the action of ARNI on a broader sample.

Main messages

  • The efficacy of sacubitril/valsartan ranges with LV EF, with patients with reduced EFs experiencing the highest notable improvements.
  • Sacubitril/valsartan demonstrated clinical and echocardiographic benefits in this retrospective study of patients with HFpEF.


Current research questions

Sacubitril/valsartan therapy was evaluated for an Indian subset of patients with NYHA class II-III, heart failure with a preserved EF of ≥50%, increased levels of natriuretic peptides, and structural heart disease. The change in NYHA class and physical signs of HF, and worsening renal function were the endpoints assessed.

What is already known on the subject

  • The clinical implications of sacubitril/valsartan for HF hospitalization and CV death are substantial in individuals with reduced EF
  • Sacubitril/valsartan could not lead to a significantly decreased rate of overall hospitalizations for HF or death from CV causes in the PARAGON-HF study among patients with HF and an EF of ≥50%.


Acknowledgments

We thank Ms. Anusha for her technical and English language editing assistance.

Ethical approval

Our institutional ethical committee approved the collection of retrospective data from the records for the publications.

Authors' contributions

PJ and KJ are consultant cardiologists who treat patients and are in charge of drafting the manuscript, collecting data, and preparing the publication. DBM is a consultant nephrologist who monitors the renal parameters of study participants. AP and HB are internists who shared their patients for our study, whereas AP and HB are internists who shared their patients for our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.  Back to cited text no. 1
    
2.
Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/Americ.  Back to cited text no. 2
    
3.
Zile MR, Baicu CF. Biomarkers of diastolic dysfunction and myocardial fibrosis: Application to heart failure with a preserved ejection fraction. Journal of Cardiovascular Translational Research [Internet]. 2013 Aug 29 [cited 2021 Jun 27];6(4):501-15. Available from: https://link.springer.com/article/10.1007/s12265-013-9472-1  Back to cited text no. 3
    
4.
McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine 2014;371:993-1004.  Back to cited text no. 4
    
5.
Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine 2019;381:1609-20.  Back to cited text no. 5
    
6.
Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation [Internet]. 2015 [cited 2021 Jun 29];131:34-42. Available from: https://pubmed.ncbi.nlm.nih.gov/25406305/  Back to cited text no. 6
    
7.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [Internet]. Vol. 37, European Heart Journal. Oxford University Press; 2016 [cited 2021 Jun 27]. p. 2129-2200m. Available from: https://academic.oup.com/eurheartj/article/37/27/2129/1748921.  Back to cited text no. 7
    
8.
Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, et al. Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: A randomized clinical trial. In: JAMA - Journal of the American Medical Association [Internet]. American Medical Association; 2019 [cited 2021 Jun 27]. p. 1077-84. Available from: https://jamanetwork.com/.  Back to cited text no. 8
    
9.
Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine [Internet]. 2019 Oct 24 [cited 2021 Jun 27];381:1609-20. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1908655.  Back to cited text no. 9
    
10.
Solomon SD, Vaduganathan M, L. Claggett B, Packer M, Zile M, Swedberg K, et al. Sacubitril/Valsartan across the Spectrum of Ejection Fraction in Heart Failure. Circulation [Internet]. 2020 Feb 4 [cited 2021 Jun 27];352–61. Available from: https://www.clinicaltrials.gov.  Back to cited text no. 10
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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